Many pathological conditions result from the adhesion of proteins or cells to extracellular matrix, membranes, or other surfaces in the body. For example, damage to tissue surfaces after peritoneal surgery can result in formation of fibrinous attachments between tissues. G. dizerega, Fertility and Sterility 61:219–235 (1994); G. Holtz, Fertility and Sterility 41:497–507 (1984). These adhesions can have severe consequences including pain, bowel obstruction, and infertility. Adhesion can also occur as a result of cataract surgery. Residual lens epithelial cells migrate onto the posterior lens capsule, resulting in formation of a secondary cataract, referred to as posterior capsule opacification, and subsequent reduction in vision. D. Apple et al., Survey of Ophthalmology 37:73–116 (1992).
These conditions result from disruption of the naturally occurring surface of a biological tissue through surgical manipulation or external injury, followed by direct contact of one such disrupted biological surface with another biological surface, and then formation of a cellular adhesion that connects the adjacent tissues. Adhesions are scar tissue bridges that often connect to opposing organs, for example, restricting organ movement and function as well as causing pain.
One approach to prevention of adhesions has involved using a physical barrier that isolates the biological surfaces from each other. Attempts to prevent surface to surface contact of tissues have met with varying levels of success. In some cases, the materials did not remain in intimate contact with the treated biological surface for a sufficient period of time. In other cases, application of the barrier materials required extensive surgical manipulation in order to cover inaccessible tissue surfaces.
Most previous work in preventing adhesions has been in the field of gynecological surgery. Solid, liquid, and gel materials have been used. Solid treatments presumably work by providing a barrier between the damaged surface and other cells. The most popular of these materials are oxidized regenerated cellulose and expanded polytetrafluoroethylene, but use of these barriers has resulted in questionable efficacy, due to the requirement for extensive surgical manipulation, sometimes including additional surgery, nonadherence of the barrier to the surface, and immune response.
Liquid materials have included high molecular weight dextran solutions, hyaluronic acid, in liquid or gel form, and Ringer's lactate. These materials may work by preventing tissue damage in the first place and/or by “floating” the tissues, but the materials can make surgical manipulation difficult and all of the materials have shown questionable efficacy.
Gel materials have included fibrin glues, a triblock copolymer of polyethylene glycol (PEG) and polypropylene glycol (PPG) which gels at physiological temperatures, and a PEG-co-lactic acid (PEG-PLA) hydrogel. U.S. Pat. Nos. 5,410,016, 5,626,863, and 5,567,435, to Hubbell et al., disclose PEG-PLA hydrogels useful for adhesion prevention. These treatments presumably work by forming a barrier over the injured surface. The fibrin glue has not been tested on lysed adhesions and it may induce inflammatory response. P. De Iaco et al., Fertility and Sterility 62:400–404 (1994); L. Adamyan et al., International Journal of Fertility 36:76–88 (1991). The triblock copolymer may be cleared from the wound site too quickly because it does not adhere specifically to surfaces. V. Montgomery Rice et al., Fertility and Sterility 59:901–906 (1993); A. Steinleitner et al., Fertility and Sterility 57:305–308 (1992). Application of the PEG-PLA hydrogel requires access to and specific treatment of each surface involved, as well as UV irradiation for the gel to form. J. West et al., Biomaterials 16:1153–1156 (1995).
Research on the prevention of posterior capsule opacification by blocking adhesion of epithelial cells to the posterior capsule has focused on causing firm contact between an implanted intraocular lens and the posterior capsule, presumably mechanically blocking the migration of cells into the visual axis of the posterior capsule. D. Apple et al., Survey of Ophthalmology 37:73–116 (1992); C. Ohadi et al., Current Opinion in Ophthalmology 2:46–52 (1991). The mechanism of this technique has yet to be confirmed, and clinical results vary.
Elbert has investigated self assembling treatments which sterically protect the underlying surfaces to allegedly prevent adhesions. D. L. Elbert et al., Chemistry and Biology 5:177–183 (1998). Elbert used copolymers containing PEG and lysine, having a comb geometry of a poly(lysine) backbone with PEG sidechains or a dendrimer geometry of PEG attached to a lysine dendrimer. The cationic copolymers may adsorb to many biological surfaces, presumably due to electrostatic interactions, while the PEG molecules presumably sterically hinder the approach of proteins and cells to the surfaces. Other research in the area has included using PEG to sterically protect surfaces by covalently adding PEG to the surface (S. Dunn et al., Pharmaceutical Research 11:1016–1022 (1994)), entrapping PEG in the surface (N. Desai et al., Biomaterials 13:505–510 (1992)), applying PEG to the surface within a gel (A. Steinleitner et al., Fertility and Sterility 57:305–308 (1992); J. West et al., Biomaterials 16:1153–1156 (1995)), and adsorbing PEG copolymers to surfaces by adding cationic moieties to the PEG (D. L. Elbert et al., Chemistry and Biology 5:177–183 (1998)).
A biocompatible material that would prevent surface to surface contact by spontaneously adhering directly to a biological surface, in sufficient quantities to protect the surface, would provide a great advantage over all of the aforementioned treatments. The material would also present a cell and protein resistant outer layer that would minimize interactions with other surfaces during healing.
It is therefore an object of the present invention to provide polymeric materials that can be applied to tissues, in a very short time period, to protect the tissues from tissue to tissue interactions, such as adhesion.
It is a further object of the present invention to provide polymeric materials which are biocompatible and resistant to degradation for a specific time period.
It is a further object of the present invention to provide methods for making and using compositions for inhibiting tissue to tissue contact and adhesion within the body.